2&#39;-(Orthochlorobenzoyl)-4&#39;-chloroglycylanilides, compositions thereof, and use as medicaments

ABSTRACT

The present invention relates to 2&#39;-(ortho-chlorobenzoyl)-4&#39;-chloroglycylanilides, compositions thereof, and their use as medicaments, e.g., as anxiolytic agents. 
     The compounds of the invention have the general formula I ##STR1## in which R represents hydrogen or alkyl, 
     R 1  and R 2  may be identical or different and are selected from hydrogen, alkyl, hydroxyalkyl, alkenyl, and alkynyl, possibly substituted by alkyl, and cycloalkyl having three to six members, possibly substituted by alkyl, with the proviso that, when one of R 1  and R 2  represents hydrogen, the other is not lower alkyl or hydroxyalkyl; and with the further proviso that R 1  and R 2  may not simultaneously represent either hydrogen or lower alkyl. R 1  and R 2  may furthermore form, with the nitrogen atom to which they are connected, a nitrogen heterocycle possibly containing a second heteroatom selected from oxygen and nitrogen.

FIELD OF INVENTION

Specifically substituted2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilides; anxiolytic agents;pharmaceutical compositions thereof; method of treating therewith.

OBJECTS OF INVENTION

It is an object of the invention to provide novel2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilides, including acidaddition salts thereof, which are useful as medicaments and particularlyuseful as anxiolytic agents; pharmaceutical compositions thereof inassociation with a pharmaceutically acceptable carrier, diluent, orexcipient, and a method of treating a patient suffering from anxiety oran anxious state by administering to the patient a compound of theinvention in an amount effective for alleviation of such condition.Other objects will become apparent hereinafter and still others will beobvious to one skilled in the art.

SUMMARY OF THE INVENTION

The present invention relates to novel derivatives of2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilides, their method ofpreparation, pharmaceutical compositions thereof, and their use asmedicaments, e.g., as anxiolytic agents.

The new compounds of the present invention have the general formula I:##STR2## in which: R represents hydrogen or alkyl, preferably methyl;

R₁ and R₂ may be identical or different and are selected from hydrogen,alkyl, hydroxyalkyl, alkenyl and alkynyl, optionally substituted one ormore times by alkyl; and cycloalkyl having three to six ring carbonatoms and optionally substituted by alkyl, provided that, when one of R₁and R₂ represents hydrogen, the other is not lower-alkyl orhydroxyalkyl; and provided further that R₁ and R₂ cannot simultaneouslyrepresent either lower-alkyl or hydrogen.

R₁ and R₂ may furthermore form, with the nitrogen atom to which they areconnected, a nitro heterocycle possibly containing a second heteroatomselected from oxygen and nitrogen.

An illustrative explanation of certain meanings given with respect tothe radicals R, R₁ and R₂ will now be indicated. First, they contain upto and including eight (8) carbon atoms in any event and, wherelower-alkyl, lower-alkenyl, or lower-alkynyl, preferably five (5) carbonatoms or less. The alkyl groups may be straight or branched-chain alkylsuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl,tert.butyl, pentyl, isopentyl, neopentyl, tert.pentyl, hexyl, isohexyl,heptyl, and octyl. "Cycloalkyl" preferably has three to six ring carbonatoms, such as cyclopropyl, cyclobutyl, cyclopentyl, methyl or propylcyclopentyl, and cyclohexyl. Alkenyl groups may representatively beallyl, butenyl, pentadienyl, or the like. Alkynyl groups mayrepresentatively be ethynyl, propargyl, or the like. Finally, thesaturated or unsaturated heterocycles are selected, for instance, fromamong the pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, imidazolidinyl,pyrazolidinyl, piperidyl, piperazinyl, and morpholinyl groups, and thelike. Hydroxyalkyl is alkyl with one or more hydroxy groups therein, atleast one of which is preferably an omega-hydroxy group, such asomega-hydroxyethyl, propyl, butyl, and amyl, 3-hydroxybutyl,3,4-hydroxyamyl, and the like. The present invention especially concernscompounds of formula I in which the radical R represents lower-alkyl,and particularly methyl.

The present invention applies also to pharmaceutically-acceptable acidaddition salts of a compound of formula I with the usualtherapeutically-acceptable acids. By way of non-limitative examples oftherapeutically or physiologically-acceptable addition salts, mentionmay be made of the salts of inorganic acids such as hydrochloric,phosphoric and sulfuric acids, and the salts of organic acids such asmaleic, succinic, fumaric, citric, and the like.

The present invention also concerns a process of preparing compounds offormula I characterized by condensing a compound of general formula II:##STR3## in which: R has the meaning given in connection with formula Iand X represents a replaceable halogen atom, with an amine of formulaIII: ##STR4## in which R₁ and R₂ have the meanings given in connectionwith general formula I. The starting materials of general formula II canbe prepared from aminobenzophenones obtained by the method of L. H.STERNBACH and R. Ian FRYER - J. Org. Chem. 27, 3781, 1962, or inaccordance with the process of French Pat. No. 78 26918, in accordancewith the following reaction sequence: ##STR5## wherein X represents areplaceable halogen atom, e.g., bromine or chlorine, and R has themeaning given previously. From the foregoing, it is apparent that tovary the alkyl group of R and R₁ in final product of formula I, it isonly necessary to vary the alkyl group R of the starting material offormula II, or to vary the alkyl group R₁ of the starting material offormula III, or both, all according to the foregoing reaction sequence.Similarly, variation of the cyclic group or groups R₁ R₂ is effectivelyaccomplished merely by variation of these groups in the startingmaterial of formula III.

The present invention also concerns the use of the compounds of generalformula I as medicaments which act on the central nervous system and, inparticular, as anxiolytic agents, as well as sedative, anticonvulsive,and hypnotic agents, and as muscle relaxants, and pharmaceuticalcompositions thereof containing the active ingredient plus the usualpharmaceutically-acceptable carrier, diluent, or excipient.

DETAILED DESCRIPTION OF INVENTION

The present invention will be described in further detail hereinafter ona basis of the following examples, which are given by way ofillustration only and are not to be construed as limiting.

EXAMPLE 1N-methyl-N-(2-hydroxyethyl)2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilide(a) Preparation of 2-bromacetamido-2',5-dichlorobenzophenone

To an iced solution of 266 g (1 mol) of2-amino-2',5-dichlorobenzophenone in 3 liters of ethyl ether there areadded, drop by drop, 90 cc (1.1 mol) of bromacetyl chloride dissolved in500 cc of ethyl ether. The batch is allowed to come to room temperature,whereupon it is evaporated to dryness and the crystalline residueextracted with petroleum ether and filtered. In this manner, 371 g ofcrystals are recovered.

Yield: 96%

Melting point: 136°-137° C.

Plate chromatography:

support: Silica gel 60 F 254 Merck

solvent: ethyl acetate/petroleum ether 30/70

development: UV and iodine

Rf: 0.82

(b) Preparation ofN-methyl-N-(2-hydroxyethyl)-2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilide

To a suspension of 139.3 g (0.36 mol) of2-bromoacetamido-2',5-dichlorobenzophenone and 2 liters of acetone thereare added 60 cc (0.76 mol) of 2-methylaminoethanol followed by heatingfor 15 hours under reflux. The reaction solvent is then evaporated todryness and the crystalline residue absorbed with isopropyl ether andextracted with a 1 N hydrochloric acid solution. The aqueous phase istreated with sodium bicarbonate and then extracted with ethyl acetate,decanted, washed with water until neutral, and dried over sodiumsulfate. After filtration and evaporation of the solvent, 130 g (yield95%) of a product of the following formula are recovered: ##STR6##

Empirical formula: C₁₈ H₁₈ Cl₂ N₂ O₃

Molecular weight: 381.26

White crystals

Melting point: 119°-120° C.

Plate chromatography:

support: silica gel 60 F 254 Merck

solvent: ethyl acetate

development: UV and iodine

Rf: 0.73

EXAMPLE 2N,N'-dimethyl-N-(2-hydroxyethyl)-2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilide(a) Preparation ofN-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-bromoacetanilide

To a solution of 56 g of 2-methylamino-2',5-dichlorobenzophenone in 400cc of ethyl acetate there are added an equal volume of ice and then 23cc of bromoacetylbromide. After stirring overnight at room temperature,300 cc of ethyl ether are added. The solvent layer is decanted, washedwith 2 N caustic soda, and then washed with water until neutral. It isthen dried over sodium sulfate, filtered, and evaporated to dryness. Theresidue is treated with petroleum ether and then recrystallized fromethyl acetate. In this way there are obtained 65 g of crystals; yield:81%.

Melting point: 86° C.

Plate chromatography:

support: Silica gel 60 F 254 Merck

solvent: ethyl acetate/petroleum ether 30/70

development: UV and iodine

Rf: 0.33

(b) Preparation ofN,N'-dimethyl-N-(2-hydroxyethyl)-2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilide

To a solution of 60.15 g (0.15 mol) ofN-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-bromoacetanilide in 500 ccof acetone there are added 25 cc (0.31 mol) of 2-methylaminoethanol,followed by heating for 2 hours under reflux. The solution is evaporatedto dryness. The residue is dissolved in 1 N hydrochloric acid and washedwith ether. The acid aqueous phase is treated with sodium bicarbonate,whereupon it is extracted with ether and washed with water untilneutral. It is dried over sodium sulfate and filtered, and the organicphase evaporated. The residue obtained is recrystallized fromhexane/ethyl acetate. There is thus recovered, in a yield of 80%, theproduct of the formula: ##STR7##

Empirical formula: C₁₉ H₂₀ Cl₂ N₂ O₃

Molecular weight: 395.27

Crystals: off white

Melting point: 79° C.

Plate chromatography:

support: silica gel 60 F 254 Merck

solvent: butanol/acetic acid/water 6/2/2

development: UV and iodine

Rf: 0.41

EXAMPLE 3 (Compound F 1933)N,N-bis-(2-hydroxyethyl)-N'-methyl-2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilidehydrochloride

To a solution of 40.1 g (01. mol) ofN-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-bromoacetanilide in 300 ccof acetone there are added 20 cc (0.2 mol) of diethanolamine, followedby agitation for 24 hours at room temperature. The reaction solvent isevaporated to dryness, the residue treated with a bicarbonate solutionand extracted with ethyl acetate. The organic phase is washed threetimes with water and dried over sodium sulfate. After filtration andevaporation there are recovered 43 g of an oil which is treated with asaturated ethanolic solution of hydrochloric acid; it is precipitatedwith ethyl ether and iced. After filtration and drying, 32 g of crystalsare recovered. Yield: 70% of product of the formula: ##STR8##

Empirical formula: C₂₀ H₂₃ Cl₃ N₂ O₄

Molecular weight: 461.77

White crystals

Melting point: 187°-188° C.

Plate chromatography:

support: silica gel 60 F 254 Merck

solvent: butanol/acetic acid/water 6/2/2

development: UV and iodine

Rf: 0.35

EXAMPLE 4N-(1,1-dimethylpropargyl)-N'-methyl-2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilidehydrochloride

To a solution of 7.37 g (0.09 mol) of 1,1-dimethylpropargyl amine in 30cc of acetone there are added 4.01 g ofN-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-bromoacetanilide. After 5hours at room temperature, the acetone is evaporated, the residuetreated with a bicarbonate solution and extraction effected with ethylacetate. After the customary treatments, as in the preceding Examples,the residual oil is treated with a saturated ethanolic solution ofhydrochloric acid. There are recovered, in a yield of 75%, 3.29 g ofcrystals of the formula: ##STR9##

Empirical formula: C₂₁ H₂₁ Cl₃ N₂ O₂

Molecular weight: 439.77

White crystals

Melting point: 176° C.

Plate chromatography:

support: silica gel 60 F 254 Merck

solvent: butanol/acetic acid/water 6/2/2

development: UV and iodine

Rf: 0.62

EXAMPLE 5 (COMPOUND F 1935)N-cyclopropyl-N'-methyl-2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilidehydrochloride

To a solution of 3.15 g (0.0078 mol) ofN-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-bromoacetanilide in 25 ccof methylene chloride there are added 1.6 cc (0.0231 mol) ofcyclopropylamine. Agitation is effected for four hours at roomtemperature; the solvent is evaporated and the residue is treated with abicarbonate solution. Extraction is effected with ethyl acetate followedby decantation, washing with water and drying over sulfate. Afterfiltration and evaporation, the residual oil obtained is treated with asaturated ethanolic solution of hydrochloric acid. In this way there isrecovered, with a yield of 85%, a product of the formula: ##STR10##

Empirical formula: C₁₉ H₁₉ Cl₃ N₂ O₂

Molecular weight: 413.73

White crystals

Melting point: 201° C.

Plate chromatography:

support: silica gel 60 F 254 Merck

solvent: butanol/acetic acid/water 6/2/2

development: UV and iodine

Rf: 0.53

Solubility: 0.3% soluble in water.

EXAMPLE 6N-cyclopentyl-N'-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-glycylanilidehydrochloride

In the manner described in Example 5, but using cyclopentylamine, thereis obtained the product of the formula: ##STR11##

Empirical formula: C₂₁ H₂₃ Cl₃ N₂ O₂

Molecular weight: 441.79

White crystals

Melting point: 210° C.

Plate chromatography:

support: silica gel 60 F 254 Merck

solvent: methanol/chloroform 50/50

development: UV and iodine

Rf: 0.78

Solubility: 0.5% soluble in water.

EXAMPLE 7 N-cyclohexyl-2'-(ortho-chlorobenzoyl)-4'-glycylanilidehydrochloride

In the manner described in Example 1, but using cyclohexylamine, thereis obtained the product of the formula: ##STR12##

Empirical formula: C₂₁ H₂₂ Cl₂ N₂ O₂

Molecular weight: 405.33

White crystals

Melting point: 115° C.

Plate chromatography:

support: silica gel 60 F 254 Merck

solvent: ethyl acetate/petroleum ether 30/70

development: UV and iodine

Rf: 0.44

Solubility: 10% soluble in DMSO, methyl pyrrolidone, ethyl acetate, DMAand chloroform.

EXAMPLE 8N-cyclohexyl-N'-methyl-2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilideacid maleate

In the manner described in Example 5, but using cyclohexylamine as amineand maleic acid as salifying agent, there is obtained a product of theformula: ##STR13##

Empirical formula: C₂₆ H₂₈ Cl₂ N₂ O₆

Molecular weight: 535.43

White crystals

Melting point: 150° C.

Plate chromatography:

support: silica gel 60 F 254 Merck

solvent: butanol/acetic acid/water 6/2/2

development: UV and iodine

Rf: 0.63

Solubility: 1% soluble in propylene glycol.

Insoluble in water. 10% soluble in DMA.

EXAMPLE 9 (COMPOUND F 1939)N-cyclohexyl-N,N'-dimethyl-2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilideacid maleate

In the manner described in Example 5, but using N-methylcyclohexylamineas amine and maleic acid as salifying agent, there is obtained theproduct of the formula: ##STR14##

Empirical formula: C₂₇ H₃₀ Cl₂ N₂ O₆

Molecular weight: 549.45

White crystals

Melting point: 192° C.

Plate chromatography:

support: silica gel 60 F 254 Merck

solvent: butanol/acetic acid/water 6/2/2

development: UV and iodine

Rf: 0.41

Solubility: Insoluble in water. 5% soluble in DMSO.

EXAMPLE 10 (COMPOUND F 1940)N-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-morpholinoacetanilide acidmaleate

In the manner described in Example 5, but using morpholine as amine andmaleic acid as salifying agent, there is obtained the product of theformula: ##STR15##

Empirical formula: C₂₄ H₂₄ Cl₂ N₂ O₇

Molecular weight: 523.37

White crystals

Melting point: 125° C.

Plate chromatography:

support: silica gel 60 F 254 Merck

solvent: butanol/acetic acid/water 6/2/2

development: UV and iodine

Rf: 0.50

Solubility: 1% soluble in water.

EXAMPLE 11N-methyl-N'-(2-methylallyl)-2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilide

In the manner described in Example 5, but using methyl allylamine, thereis obtained a product of the formula: ##STR16##

Empirical formula: C₂₀ H₂₀ Cl₂ N₂ O₂

Molecular weight: 391.3

White crystals

Plate chromatography:

support: silica gel 60 F 254 Merck

solvent: butanol/acetic acid/water 6/2/2

development: UV and iodine

Rf: 0.67

EXAMPLE 12N-cyclohexyl-N,N'-diethyl-2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilideacid maleate and other N,N'-dialkyl variations

In the manner described in Example 5, but using N-ethylcyclohexylamineas amine, maleic acid as salifying agent, andN-ethyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-bromoacetanilide asstarting material of Formula II, there is obtained the above-identifiedproduct.

Similarly, in the manner described in Example 5, but usingN-propylcyclohexylamine as amine, and maleic acid as salifying agent,there is obtained the productN-cyclohexyl-N-propyl-N'-methyl-2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilideacid maleate.

In substantially the same manner as described in Example 5, but usingN-methylcyclohexylamine as amine, maleic acid as salifying agent, andN-amyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-bromoacetanilide for thestarting material of Formula II, there is obtained the productN-cyclohexyl-N-methyl-N'-amyl-2'-(ortho-chlorobenzoyl)-4'-chloro-glycylanilideacid maleate.

Similarly, in the manner described in Example 5, but usingN-ethylcyclopropylamine, there is obtained the compoundN-cyclopropyl-N-ethyl-N'-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-glycylanilidehydrochloride.

In the same manner as described in Example 5, but using morpholine, asamine, maleic acid as salifying agent, andN-butyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-bromoacetanilide asstarting material of Formula II, there is obtained the productN-butyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-morpholinoacetanilide acidmaleate.

In the same manner, by varying the substituents R and R₁ in the startingmaterial of Formula II and in the amine reactant of Formula III,numerous additional variations in the R and R₁ alkyl groups areconveniently obtained.

EXAMPLE 13N-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-(4"-methylpiperazino)acetanilideacid maleate

In the manner described in Example 5, but using N-methylpiperazine asamine and maleic acid as salifying agent, the above-identified productis produced.

EXAMPLE 14N-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-pyrrolidinoacetanilideacid maleate and additional cyclic variations of R₁ and R₂

In the manner described in Example 5, but using pyrrolidine as amine andmaleic acid as salifying agent, the above-identified product isproduced.

In the same manner as given in Example 5, but using piperidine as amineand maleic acid as salifying agent, there is obtained the productN-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-piperidino-acetanilideacid maleate.

In the same manner as given in Example 5, but using pyrrolidine asamine, maleic acid as salifying agent, andN-propyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-bromoacetanilide asstarting material of Formula II, there is obtained the productN-propyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-pyrrolidinoacetanilideacid maleate.

In the same manner as given in Example 5, but using imidazolidineinstead of cyclopropylamine, there is obtained the productN-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-imidazolidino-acetanilidehydrochloride.

In exactly the same manner, but substituting pyrazolidine forimidazolidine, there is obtained the productN-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-pyrazolidinoacetanilidehydrochloride.

In exactly the same manner, but substituting pyrrole, imidazole,pyrazole, isoxazole, pyridine, pyrazine, pyrimidine, or pyridazine forthe cyclopropylamine of Example 5, the following products are obtained:

N-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-pyrrolinoacetanilidehydrochloride,

N-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-imidazolinoacetanilidehydrochloride,

N-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-pyrazolinoacetanilidehydrochloride,

N-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-isoxazolinoacetanilidehydrochloride,

N-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-pyridinoacetanilidehydrochloride,

N-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-pyrazinoacetanilidehydrochloride,

N-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-pyrimidinoacetanilidehydrochloride, and

N-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-pyridazinoacetanilidehydrochloride.

Similarly, by substituting additional heterocyclic amines for themorpholine of Example 10 or the cyclopropylamine of Example 5,additional compounds within the scope of the invention are obtained,having additional cyclic variations of the R₁ and R₂ substituents.

EXAMPLE 15N-methylcyclopentyl-N'-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-glycylanilidehydrochloride

In the manner of Example 6, but substituting methylcyclopentylamine forcyclopentylamine, there is obtained the above-identified product.

EXAMPLE 16N-ethylcyclopentyl-N'-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-glycylanilidehydrochloride

In the manner of Example 6, but substituting ethylcyclopentylamine forthe cyclopentylamine of Example 6, there is obtained theabove-identified product.

EXAMPLE 17N-ethylcyclohexyl-N'-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-glycylanilidehydrochloride

In the same manner as given in Example 6, but using ethylcyclohexylamineinstead of the cyclopentylamine there employed, there is obtained theabove-identified product.

EXAMPLE 18N-cyclohexyl-N,N'-diamyl-2'-(ortho-chlorobenzoyl)-4'-chloro-glycylanilideacid maleate

In the same manner as given in Example 5, but usingN-amylcyclohexylamine as amine, maleic acid as salifying agent, andN-amyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-bromoacetanilide as startingmaterial of Formula II, there is obtained the above-identified product.

EXAMPLE 19N-methyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-ethylmorpholinoacetanilideacid maleate

In the manner of Example 5, but using ethylmorpholine as amine andmaleic acid as salifying agent, there is obtained the above-identifiedproduct.

EXAMPLE 20N-propyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-methylmorpholinoacetanilideacid maleate

In the manner of Example 5, but using methylmorpholine as amine, maleicacid as salifying agent, andN-propyl-2'-(ortho-chlorobenzoyl)-4'-chloro-2-bromoacetanilide asstarting material of Formula II, there is obtained the above-identifiedproduct.

PHARMACOLOGY AND TOXICOLOGY

The compounds of the present invention, which exert remarkable activityon the central nervous system, can therefore be administered to man orto animal orally or by injection in the form of a free base or else inthe form of a therapeutically acceptable salt. The new derivativesobtained in the foregoing manner, which are bases, can be converted intoaddition salts with acids, which form part of the invention. Theaddition salts can be obtained by the reaction of the new derivativeswith acids in suitable solvents such, for example, as shown by theexamples. As acids used for the formation of these addition salts theremay be mentioned, in the mineral series: hydrochloric, hydrobromic,methanesulphonic, sulphuric and phosphoric acid; in the organic series:acetic, propionic, maleic, fumaric, tartaric, citric, oxalic, benzoicacid, to name a few. The invention accordingly also relates to the saltswith organic or inorganic acids, especially lipophilic acids, e.g.,fatty acids having 14 to 22 carbon atoms, inclusive, which are linear orbranched, saturated or unsaturated, including palmitic, linoleic,linolenic, and oleic acids, and the like, as well as of the naphthoictype, especially pamoic acid, in addition to the usual organic andinorganic acids of the type already mentioned. The selection of the freebase or acid addition salt thereof and preparation of the desired acidaddition salt of a compound in any particular case will be apparent andfully within the ability of one skilled in the art. The novel compoundsare frequently used in the form of their pharmaceutically acceptableacid addition salts, e.g., their hydrochlorides, hydrobromides, or thelike. The salt is usually the best form for pharmaceutical formulations.Innumerable other pharmaceutically-acceptable acid addition salts can beprepared from the hydrochlorides via the free bases in conventionalmanner.

By way of simple illustration, there will be set forth below a fewresults of the various toxicological and pharmacological tests carriedout on the compounds of the invention.

(a) Toxicity study

The compounds of the present invention were subjected to toxicityverifications. The toxicity of certain compounds, determined by thefifty percent lethal dose, is set forth in the following table. It wasdetermined on lots of ten mice by oral administration and calculated bythe method of MILLER and TAINTER (Proc. Soc. Exper. Biol. Med., 1944,57, 261).

(b) Activity in the Rota Rod test

This test is carried out on male mice of Swiss strain.

The mice are placed on a wooden rod of a diameter of three cm, rotatingat the rate of five rpm. The mice which can remain on the rod for atleast three minutes during successive tests are selected and collectedin groups of ten for the test of each dose.

If the mouse falls from the rod in less than two minutes, the compoundtested is considered effective.

The results are expressed in ED₅₀ in accordance with N. W. DUNHAM and T.S. MIVA (J. Amer. Pharm. Asso., 1957, 46, 208).

(c) Antagonistic activity to pentetrazol

This test is carried out on a group of ten male mice of Swiss strain.Within fifteen minutes after subcutaneous injection of 125 mg/kg ofpentetrazol, the mice have tonic convulsions resulting in death. For thetest, the compounds are administered orally sixty minutes before theinjection of pentetrazol. The animals are observed for two hours afteradministration of the pentetrazol.

The results are expressed by the ED₅₀ dose in accordance with GOODMANNet al. (J. Pharmacol. 108, 1953).

    ______________________________________                                        TABLE OF RESULTS                                                               ##STR17##                                                                                             ROTA                                                               TOXICITY   ROD      PENTE-                                                    per os     per os   TRAZOL                                                    DE.sub.50  DE.sub.50                                                                              per os                                      Y             mg/kg      mg/kg    DE.sub.50 mg/kg                             ______________________________________                                         ##STR18##      750      17       0.9                                          ##STR19##    ≃1000                                                                      15       0.5                                          ##STR20##      420      19       1                                            ##STR21##    >1000       7       0.3                                          ##STR22##      750      16       1.9                                          ##STR23##    >1000      20       0.7                                          ##STR24##    >1000      21       0.8                                          ##STR25##    >1000      20       0.8                                          ##STR26##    >1000      10       0.4                                         ______________________________________                                    

On a basis of their pharmacological properties and their low toxicity,these chemical compounds can be used in therapy for the treatment ofanxiety and neuroses.

These compounds and their therapeutically acceptable acid addition saltscan be used as medicaments, for instance, in the form of pharmaceuticalpreparations adapted for oral or parenteral administration in admixturewith, for instance, water, lactose, gelatin, starches, magnesiumstearate, talc, vegetable oils, gums, polyalkylene glycols, vaseline,etc. These preparations may be in solid form, for instance, in the formof tablets, pills, capsules, etc., or in liquid form, for example,solutions, suspensions or emulsions.

Pharmaceutical preparations in a form suitable for injection arepreferred. These preparations may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containadjuvants, for example, preservatives, stabilizers, wetting oremulsifying agents, buffering compounds, etc.

The doses in which the active compounds and their therapeuticallycompatible acid addition salts can be administered can vary with wideranges depending on the size, weight, and condition of the patient. Adaily dose of about 0.01 mg to 1 mg/kg of body weight is, however,preferred.

The pharmaceutical compositions of the invention can be used in internalmedicine, as anxiolytic agents, i.e., for the treatment of anxietystates of whatever origin, for instance in the treatment of organicpathological conditions such as arterial hypertension and coronaritis,accompanied and aggravated by a state of anxiety or in psychosomaticmedicine, for instance for the treatment of asthma, gastro-duodenalulcers, colonopathy and other functional digestive ailments, accompaniedby or resulting from anxiety, as well as in psychiatry, for instance fortreatment of anxiety conditions of agitation in psychotic subjects.

For these various purposes, the compounds of the invention are, ofcourse, administered in doses which vary with their nature, with themethod of administration, and with the treatment desired.

Pharmaceutical preparations containing these active principles may beadministered orally, parenterally, rectally and locally, in each casefor their intended purpose.

For oral administration tablets, capsules and elixirs may be used, theunit dose being 5 to 500 mg, in accordance with a usual maximum dailydose in man of 500 mg. For rectal administration these quantities areusually 100 to 500 mg respectively.

The pharmaceutical compositions may also contain other pharmaceuticallyand therapeutically compatible active principles.

A few examples of pharmaceutical preparations which contain arepresentative active principle forming an object of the invention aregiven below, by way of illustration only and not by way of limitation:

(a) tablets F 1933, 1935, 1939 or 1940 150 mg+excipient

(b) suppository, adult, strong: F 1933, 1935, 1939 or 1940 200mg+suppository excipient

(c) capsules: F 1933, 1935, 1939 or 1940 75 mg plus excipient 100 mg; orF 1933, 1935, 1939 or 1940 alone.

For oral use, the compounds are usually administered as tablets,solutions, suspensions, or the like, in which they are present togetherwith usual pharmaceutical carriers, excipients, binders, and the like.For example, tablets may be prepared conventionally by compounding oneof the new compounds with customary carriers and adjuvants, e.g., talc,magnesium stearate, starch, lactose, gelatin, gums and the like. Intheir most advantageous form, then, the compositions of the presentinvention will contain a non-toxic pharmaceutical carrier in addition tothe active ingredient. Exemplary carriers are: Solids: lactose,magnesium stearate, calcium stearate, starch, terra alba, dicalciumphosphate, sucrose, talc, stearic acid, gelatin, agar, pectin, acacia,or other usual excipient; Liquids: peanut oil, sesame oil, olive oil,water, elixir, or other usual excipient. The active agents of theinvention can usually be most conveniently administered in suchcompositions containing about 0.01 to 67 percent, preferably 0.04 to12.15 percent, by weight of the active ingredient. Such formulations arerepresentatively illustrated in U.S. Pat. No. 3,402,244.

A wide variety of pharmaceutical forms suitable for many modes ofadministration and dosages may be employed. For oral administration, theactive ingredient and pharmaceutical carrier may, for example, take theform of a granule, pill, tablet, lozenge, elixir, syrup, or other liquidsuspension or emulsion; and for rectal administration, a suppository.For topical or dermatological use and administration, an ointment,salve, solution, or suspension of usual type may be employed.

The method of using the compounds of the present invention comprisesadministering a compound of the invention, preferably admixed with apharmaceutical carrier, for example, in the form of any of theabove-mentioned compositions, or filled into a capsule, to alleviate oneor more of the foregoing enumerated abnormal conditions and symptoms,especially anxiety, in a living animal body, whether human or domesticanimal, for example, the afore-mentioned anxiety types. The compoundsare subject to usual variations in optimum daily and unit dosages, dueto patient body weight, condition, and ancillary factors, and theinvention therefore should not be limited by the exact ranges stated.The exact dosage, both unit and daily, will of course as usual have tobe determined according to established veterinary and medicalprinciples.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds, compositions, orprocedures shown and described, as obvious modifications and equivalentswill be apparent to one skilled in the art, and the invention istherefore to be limited only by the scope of the appended claims.

We claim:
 1. 2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilides selectedfrom compounds having the formula I: ##STR27## in which: R representshydrogen or lower-alkyl;R₁ and R₂ are lower-hydroxyalkyl, andpharmaceutically acceptable inorganic or organic acid addition saltsthereof.
 2. A compound of claim 1 which isN,N-bis-(2-hydroxyethyl)-N'-methyl-2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilideor a pharmaceutically-acceptable acid addition salt thereof.
 3. Acompound of claim 1 which isN,N-bis-(2-hydroxyethyl)-N'-methyl-2'-(ortho-chlorobenzoyl)-4'-chloroglycylanilidehydrochloride.